Spatial determinates of effector and memory CD8⁺ T cell fates

The lymph node plays a critical role in mounting an adaptive immune response to infection, clearance of foreign pathogens, and cancer immunosurveillance. Within this complex structure, intranodal migration is vital for CD8⁺ T cell activation and differentiation. Combining tissue clearing and volumetric light sheet fluorescent microscopy of intact lymph nodes has allowed us to explore the spatial regulation of T cell fates. This has determined that short-lived effector (T_SLEC ) are imprinted in peripheral lymph node interfollicular regions, due to CXCR3 migration. In contrast, stem-like memory cell (T_SCM ) differentiation is determined in the T cell paracortex. Here, we detail the inflammatory and chemokine regulators of spatially restricted T cell differentiation, with a focus on how to promote T_SCM . We propose a default pathway for T_SCM differentiation due to CCR7-directed segregation of precursors away from the inflammatory effector niche. Although volumetric imaging has revealed the consequences of intranodal migration, we still lack knowledge of how this is orchestrated within a complex chemokine environment. Toward this goal, we highlight the potential of combining microfluidic chambers with pre-determined complexity and subcellular resolution microscopy.